EP2526092B1 - Amino-heteraryl verbindungen als beta-secretase modulatoren und verfahren zu ihrer verwendung - Google Patents

Amino-heteraryl verbindungen als beta-secretase modulatoren und verfahren zu ihrer verwendung Download PDF

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EP2526092B1
EP2526092B1 EP11702316.8A EP11702316A EP2526092B1 EP 2526092 B1 EP2526092 B1 EP 2526092B1 EP 11702316 A EP11702316 A EP 11702316A EP 2526092 B1 EP2526092 B1 EP 2526092B1
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morpholinoquinolin
amino
methylphenyl
methanone
mmol
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French (fr)
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EP2526092A1 (de
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Nick A Paras
James Brown
Yuan Cheng
Stephen Hitchcock
Ted Judd
Patricia Lopez
Ana Elena Minatti
Thomas Nixey
Timothy Powers
Christopher M. Tegley
Qiufen Xue
Bryant Yang
Wenge Zhong
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Amgen Inc
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Amgen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the invention relates generally to new compounds, pharmaceutical compositions compounds for use, to treat Beta-Secretase mediated diseases and conditions, including Alzheimer's disease, plaque formation in the brain as well as in the peripheral central nerveous system and disorders related thereto.
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • AD is generally characterized by the progressive decline of memory, reasoning, judgement and orientation.
  • motor, sensory, and vocal abilities are affected until there is global impairment of multiple cognitive functions.
  • the loss of cognitive function occurs gradually, typically leading to a diminished cognition of self, family and friends.
  • Patients with severe cognitive impairment and/or diagnosed as end-stage AD are generally bedridden, incontinent, and dependent on custodial care.
  • the AD patient eventually dies in about nine to ten years, on average, after initial diagnosis. Due to the incapacitating, generally humiliating and ultimately fatal effects of AD, there is a need to effectively treat AD upon diagnosis.
  • AD Alzheimer's disease
  • beta amyloid plaque formation supports the "amyloid cascade hypothesis" which conveys the thought that AD is caused by the formation of characteristic beta amyloid peptide (A-beta), or A-beta fragments thereof, deposits in the brain (commonly referred to as beta amyloid "plaques” or “plaque deposits”) and in cerebral blood vessels (beta amyloid angiopathy).
  • a wealth of evidence suggests that beta-amyloid and accompanying amyloid plaque formation is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder.
  • the second change in AD is the formation of intraneuronal tangles, consisting of an aggregate form of the protein tau. Besides being found in patients with AD, intraneuronal tangles are also found in other dementia-inducing disorders. Joachim et al., Alz. Dis. Assoc. Dis., 6:7-34 (1992 ).
  • Amyloid containing plaques and vascular amyloid angiopathy were also found in the brains of individuals with Down's Syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders.
  • A-beta formation is a causative precursor or factor in the development of AD. More specifically, deposition of A-beta in areas of the brain responsible for cognitive factors is believed to be a major factor in the development of AD.
  • Beta amyloid plaques are primarily composed of amyloid beta peptide (A-beta peptide).
  • A-beta peptide is derived from the proteolytic cleavage of a large transmembrane amyloid precursor protein (APP), and is a peptide ranging in about 39-42 amino acid residues.
  • A-beta 42 (42 amino acids long) is thought to be the major component of these plaque deposits in the brains of Alzheimer's Disease patients. Citron, Trends in Pharmacological Sciences, 25(2):92-97 (2004 ).
  • plaques appear in some variants of Lewy body dementia and in inclusion body myositis, a muscle disease.
  • a ⁇ also forms aggregates coating cerebral blood vessels in cerebral amyloid angiopathy.
  • These plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers, a protein fold shared by other peptides such as prions associated with protein misfolding diseases.
  • Research on laboratory rats suggest that the two-molecule, soluble form of the peptide is a causative agent in the development of Alzheimer's and that the two-molecule form is the smallest synaptotoxic species of soluble amyloid beta oligomer.
  • Shnakar, G.M. Nature Medicine (June 22, 2008 ) online doi 10:1038 nm 1782.
  • Beta secretase (BACE, also commonly referred to as memapsin) is thought to first cleave APP to generate two fragments: (1) a first N-terminus fragment (beta APP) and (2) a second C-99 fragment, which is subsequently cleaved by gamma secretase to generate the A-beta peptide.
  • APP has also found to be cleaved by alpha-secretase to produce alpha-sAPP, a secreted form of APP that does not result in beta-amyloid plaque formation.
  • BACE is an aspartyl protease enzyme comprising 501 amino acids and responsible for processing APP at the beta-secretase specific cleavage site.
  • BACE is present in two forms, BACE 1 and BACE 2, designated as such depending upon the specific cleavage site of APP.
  • Beta secretase is described in Sinha et al., Nature, 402:537-554 (1999 ) (p510) and PCT application WO 2000/17369 . It has been proposed that A-beta peptide accumulates as a result of APP processing by BACE.
  • in vivo processing of APP at the beta secretase cleavage site is thought to be a rate-limiting step in A-beta production.
  • inhibition of the BACE enzyme activity is desirable for the treatment of AD.
  • BACE knockout mice do not produce beta-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. Cole, S.L., Vasser, R., Molecular Degeneration 2:22, 2007 . When crossed with transgenic mice that over express APP, the progeny of BACE deficient mice show reduced amounts of A-beta in brain extracts as compares with control animals ( Luo et al., Nature Neuroscience, 4:231-232 (2001 )). The fact that BACE initiates the formation of beta-amyloid, and the observation that BACE levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE inhibition thus reducing beta-amyloid and its associated toxicities.
  • Dimebolin appears to operate through multiple mechanisms of action, both blocking the action of neurotoxic beta amyloid proteins and inhibiting L-type calcium channels modulating the action of AMPA and NMDA glutamate receptors.
  • inhibition of cleavage or fragmentation of beta amyloid protein via the beta secretase pathway may provide a therapeutic method for treating AD and other beta amyloid or plaque related disorders.
  • WO-A-2009097401 discloses 2-amino-quinoline derivatives, pharmaceutical compositions containing them and their use in the treatment of Alzheimer's disease (AD), mild cognitive impairment, senility and/or dementia. Despite these efforts, there is always a need to find new compounds which may effectively treat such plaque-related conditions and disorders, such as AD.
  • the present invention provides a new class of compounds useful for the modulation of beta secretase activity.
  • the compounds of the invention are useful for the regulation or reduction of the formation of A-beta peptide and, consequently, the regulation and/or reduction of beta amyloid plaque formation on the brain.
  • the compounds are useful for the treatment of Alzheimer's disease and other beta secretase and/or plaque mediated disorders.
  • the compounds are useful for the prophylaxis and/or treatment, acute and/or chronic, of AD and other diseases or conditions involving the deposition or accumulation of beta amyloid peptide, and formation of plaque, on the brain.
  • the compounds provided by the invention including stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, are generally defined by Formula I wherein ring A, B 1 , B 2 , B 3 , L, R 1 , R 2 , ring Z, m and n of Formula I are defined herein below.
  • the invention also provides compounds of sub-formulas of Formula I, as well as procedures for making compounds of Formula I.
  • the invention further provides pharmaceutical compositions, which comprise one or more compounds of the invention, compounds for use in the treatment of beta secretase mediated diseases, such as AD, using the compounds and compositions of the invention.
  • the invention provides a pharmaceutical composition comprising an effective dosage amount of a compound of Formula I in association with at least one pharmaceutically acceptable excipient.
  • the compounds including stereoisomers, tautomers or pharmaceutically acceptable salts thereof, are generally defined by Formula I wherein
  • the compounds of Formula I include compounds wherein ring A is an optionally substituted 5- or 6-membered aryl or heteroaryl, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include compounds wherein ring A is an optionally substituted 5-membered heteroaryl, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include compounds wherein ring A is an optionally substituted 6-membered heteroaryl, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include compounds wherein ring A is an optionally substituted 6-membered aryl, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include compounds wherein ring A is an optionally substituted phenyl, pyridine, pyrimidine, triazine, pyrazine, pyridazine, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, isothiazole, pyrrole, furan or thiophene, in conjunction with any of the above or below embodiments.
  • ring A is an optionally substituted phenyl, pyridine, pyrimidine, triazine, pyrazine, pyridazine, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, isothiazole, pyrrole, furan or thiophene, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include compounds wherein ring A is an optionally substituted phenyl, pyridine, pyrimidine, triazine, pyrazinyl, pyridazinyl or thiophene, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include compounds wherein each of B 1 , B 2 and B 3 , independently, is N, -CF, -CCH 3 or CH, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include compounds wherein each of B 1 , B 2 and B 3 , independently, is -CF, -CCH 3 or CH, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include compounds wherein each of B 1 , B 2 and B 3 , independently, is CH, in conjunction with any of the above or below embodiments.
  • the invention provides compounds, including stereoisomers, tautomers or pharmaceutically acceptable salts thereof, generally defined by Formula I-A wherein
  • the invention provides compounds, including stereoisomers, tautomers or pharmaceutically acceptable salts thereof, generally defined by Formula I-A-I wherein
  • the compounds of Formulas I, I-A and I-A-I include compounds wherein ring Z is , each ring of which is optionally substituted independently with 1-5 aubstituents of R 2 , in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A and I-A-I include compounds wherein each R 1 , independently, is a fully saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each ring of said ring system is optionally substituted independently with 1-5 substituents of R 3 , in conjunction with any of the above or below embodiments.
  • Formulas I, I-A and I-A-I include compounds wherein each of R 1 is F, Cl, CF 3 , OCF 3 , methyl, ethyl, CN, OH, OCH 3 , SCH 3 , NHCH 3 or C(O)CH 3 , in conjunction with any of the above or below embodiments.
  • Formulas I, I-A and I-A-I include compounds wherein each R 1 independently, is F, Cl, Br, CF 3 , OCF 3 , C 1-6 -alkyl, CN, OH, -OC 1-6 -alkyl, - S(O) n C 1-6 -alkyl, -NH 2 , CN, -NHC 1-6 -alkyl, -C(O)C 1-6 -alkyl, -C(O)C 1-6 cycloalkyl, -C(O)-tetrahydropyrrole, in conjunction with any of the above or below embodiments.
  • Formulas I, I-A and I-A-I include compounds wherein each R 2 , independently, is H, C 1-3 alkyl or halo, in conjunction with any of the above or below embodiments.
  • Formulas I, I-A and I-A-I include compounds wherein each R 2 , independently, is H, CH 3 , CH 2 CH 3 , F or Cl, in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A and I-A-I include compounds wherein each R 2 , independently, is halo, haloalkyl, haloalkoxyl, CN, NO 2 , NH 2 , OH, oxo, C 1-6 -alkyl, -OC 1-6 -alkyl, -S(O) n C 1-6 -alkyl, -NHC 1-6 -alkyl, aryl or-C(O)NR a R b wherein R a is H or C 1-6 alkyl and R b is H or C 1-6 alkyl, in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A and I-A-I include compounds wherein each R 2 independently, is F, Cl, CF 3 , OCF 3 , C 1-6 -alkyl, CN, OH, -OC 1-6 -alkyl, -OCF 3 , -NH 2 , NHCH 3 or -C(O)CH 3 , in conjunction with any of the above or below embodiments.
  • the invention provides compounds, including stereoisomers, tautomers or pharmaceutically acceptable salts thereof, generally defined by Formula I-B-I wherein
  • the compounds of Formulas I, I-A, I-A-I and I-B-I include compounds wherein m is 0, 1, 2, 3, 4 or 5, in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A, I-A-I and I-B-I include compounds wherein m is 0, 1, 2 or 3, in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A, I-A-I and I-B-I include compounds wherein m is 0, 1 or 2, in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A, I-A-I and I-B-I include compounds wherein m is 0 or 1, in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A, I-A-I and I-B-I include compounds wherein n is 0, 1, 2, 3, 4 or 5, in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A, I-A-I and I-B-I include compounds wherein n is 0, 1, 2 or 3, in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A, I-A-I and I-B-I include compounds wherein n is 0, 1 or 2, in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A, I-A-I and I-B-I include compounds wherein n is 0 or 1, in conjunction with any of the above or below embodiments.
  • the compounds of Formulas I, I-A, I-A-I and I-B-I include compounds wherein n is 0, in conjunction with any of the above or below embodiments.
  • Formulas I, I-A, I-A-I and I-B-I include compounds wherein R 3 is a fully saturated or partially or fully unsaturated 5- or 6-membered monocyclic or bicyclic ring formed of carbon atoms, said ring optionally including 1-4 heteroatoms selected from O, N, or S, wherein the C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl and ring are optionally substituted, independently, with 1-5 substituents of halo, haloalkyl, haloalkoxyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, buty
  • Formulas I, I-A, I-A-I and I-B-I include compounds wherein R 3 is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl and pyranyl, said ring optionally substituted, independently, with 1-5 substituents of halo, haloalkyl, hal
  • Formulas I I, I-A, I-A-I and I-B-I include compounds wherein R 3 is halo, haloalkyl, haloalkoxyl, C 1-6 -alkyl, C 2-6 alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, or a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolidinyl, oxazolinyl, isoxazolin
  • Formulas I, I-A, I-A-I and I-B-I include compounds wherein R 3 is C 1-4 alkyl substituted with 1-3 substituents of F, Cl, Br, I, CF 3 , C 2 F 5 and haloalkoxyl, or R 4 is F, Cl, Br, I, CF 3 , C 2 F 5 , haloalkoxyl, CN, OH, OC 1-6 -alkyl, SC 1-6 -alkyl, SC 1-6 -alkyl, S(O) o C 1-6 -alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl wherein the cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted independently with 1-5 substituents of F, Cl, Br, haloalkyl, haloalkoxyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl,
  • Formulas I, I-A, I-A-I and I-B-I include compounds wherein R 3 is F, Cl, Br, I, CF 3 , C 2 F 5 , haloalkoxyl, C 1-6 -alkyl, CN, OH, OC 1-6 -alkyl, SC 1-6 -alkyl, SC 1-16 -alkyl, S(O) o C 1-6 -alkyl wherein o is 0, 1 or 2, NHC 1-6 -alkyl or C(O)C 1-6 -alkyl, in conjunction with any of the above or below embodiments.
  • the invention provides the compound of Formula I, I-A, I-A-I or I-B-I, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from any of the compound examples 1-221, presented hereinbelow in Table 1.
  • the invention provides each of the Examplary compounds, and stereoisomers, tautomers and pharmaceutically acceptable salts, thereof described herein.
  • the invention provides the exemplified compounds described herein, and stereoisomers and pharmaceutically acceptable salt forms of each thereof.
  • C ⁇ - ⁇ alkyl when used either alone or within other terms such as “haloalkyl” and “alkylamino”, embraces linear or branched radicals having ⁇ to ⁇ number of carbon atoms (such as C 1 -C 10 ; C 1 -C 6 ; or C 1 -C 4 ). Unless otherwise specified, one or more carbon atoms of the "alkyl” radical may be substituted, such as with a cycloalkyl moiety.
  • alkyl radicals include methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, ethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, n-propyl, isopropyl, n-butyl, cyclopropylbutyl, isobutyl, sec -butyl, tert- butyl, pentyl, isoamyl, and hexyl.
  • C ⁇ - ⁇ alkenyl when used alone or in combination, embraces linear or branched radicals having at least one carbon-carbon double bond in a moiety having a number of carbon atoms in the range from ⁇ and ⁇ . Included within alkenyl radicals are “lower alkenyl” radicals having two to about six carbon atoms and, for example, those radicals having two to about four carbon atoms. Examples of alkenyl radicals include, without limitation, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl and “lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations, as appreciated by those of ordinary skill in the art.
  • C ⁇ - ⁇ alkynyl when used alone or in combination, denotes linear or branched radicals having at least one carbon-carbon triple bond in a moiety having a number of carbon atoms in the range from ⁇ and ⁇ .
  • alkynyl radicals include "lower alkynyl” radicals having two to about six carbon atoms and, for example, lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include, without limitation, ethynyl, propynyl (propargyl), and butynyl.
  • C ⁇ - ⁇ -alkyl when used with other terms such as "wherein 1, 2 or 3 carbon atoms of said C ⁇ - ⁇ -alkyl, C ⁇ - ⁇ -alkenyl or C 2 ⁇ - ⁇ -alkynyl is optionally replaced with a heteroatom selected from O, S, S(O), S(O) 2 and N" embraces linear or branched radicals wherein one or more of the carbon atoms may be replaced with a heteroatom.
  • C ⁇ - ⁇ alkoxyl when used alone or in combination, embraces linear or branched oxygen-containing alkyl radicals each having ⁇ to ⁇ number of carbon atoms (such as C 1 -C 10 ).
  • alkoxy and alkoxyl when used alone or in combination, embraces linear or branched oxygen-containing radicals each having alkyl and substituted alkyl portions of one or more carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals or with other substitution. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, fluoropropoxy and cyclopropylmethoxy.
  • aryl when used alone or in combination, means a carbocyclic aromatic moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner. Every ring of an "aryl" multi-ring system need not be aromatic, and the ring(s) fused to the aromatic ring may be partially or fully unsaturated and include one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl, and benzodioxazinyl.
  • the "aryl” group may be substituted, such as with 1 to 5 substituents including lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino. Phenyl substituted at two carbons with -O-CH 2 -O- or -O-CH 2 -CH 2 -O- form an aryl benzodioxolyl substituent.
  • cycloalkyl also referred to herein as “carbocyclic” or “carbocyclyl”, when used alone or in combination, means a partially or fully saturated ring moiety formed of carbon atoms and comprising one ("monocyclic"), two (“bicyclic") or even three (“tricyclic") rings wherein such rings may be attached together in a fused manner.
  • saturated cycloalkyl radicals include saturated 3 to 6-membered monocyclic groups such as cyclopropane, cyclobutane, cyclopentane and cyclohexane.
  • ring and ring system refer to a ring comprising the delineated number of atoms, the atoms being carbon or, where indicated, a heteroatom such as nitrogen, oxygen or sulfur. Where the number of atoms is not delineated, such as a “monocyclic ring system” or a “bicyclic ring system", the numbers of atoms are 3-8 for a monocyclic and 6-12 for a bicyclic ring.
  • the ring itself, as well as any substitutents thereon, may be attached at any atom that allows a stable compound to be formed.
  • nonaromatic ring or ring system refers to the fact that at least one, but not necessarily all, rings in a bicyclic or tricyclic ring system is nonaromatic.
  • cycloalkenyl when used alone or in combination, means a partially or fully saturated cycloalkyl containing one, two or even three rings in a structure having at least one carbon-carbon double bond in the structure.
  • cycloalkenyl groups include C 3 -C 6 rings, such as compounds including, without limitation, cyclopropene, cyclobutene, cyclopentene and cyclohexene.
  • the term also includes carbocyclic groups having two or more carbon-carbon double bonds such as "cycloalkyldienyl” compounds.
  • cycloalkyldienyl groups include, without limitation, cyclopentadiene and cycloheptadiene.
  • halo when used alone or in combination, means halogens such as fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms.
  • haloalkyl when used alone or in combination, embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.
  • this term includes monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as a perhaloalkyl.
  • a monohaloalkyl radical for example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl (CF 3 ), chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perfluoroalkyl refers to alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
  • heteroaryl means a fully unsaturated (aromatic) ring moiety formed from carbon atoms and having one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • the ring moiety or ring system may contain one ("monocyclic"), two ("bicyclic") or even three (“tricyclic") rings wherein such rings are attached together in a fused manner. Every ring of a “heteroaryl” ring system need not be aromatic, and the ring(s) fused thereto (to the heteroaromatic ring) may be partially or fully saturated and optionally include one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl does not include rings having ring members of -O-O-, -O-S- or -S-S-.
  • unsaturated heteroaryl radicals include unsaturated 5- to 6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] and tetrazole; unsaturated 7- to 10- membered heterobicyclyl groups containing 1 to 4 nitrogen atoms, including for example, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, and aza-quinazolinyl; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom,
  • heterocyclic when used alone or in combination, means a partially or fully saturated ring moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner, formed from carbon atoms and including one or more heteroatoms selected from N, O or S.
  • saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • morpholinyl saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.
  • heterocycle also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • heterocyclic radicals include five to ten membered fused or unfused radicals.
  • Examples of partially saturated and fully saturated heterocyclyls include, without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoly
  • a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S" as used herein is intended to encompass all monocyclic and bicyclic rings as small as three atoms to as large as 12 atoms in size, including both carbocyclic rings and heterocyclic, aromatic and non-aromatic rings.
  • the non-aromatic rings may be partially or fully saturated in nature.
  • alkylamino includes "N-alkylamino" where amino radicals are independently substituted with one alkyl radical.
  • Preferred alkylamino radicals are "lower alkylamino" radicals having one to six carbon atoms. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Examples of such lower alkylamino radicals include N-methylamino, and N-ethylamino, N-propylamino, and N-isopropylamino.
  • dialkylamino includes "N, N-dialkylamino" where amino radicals are independently substituted with two alkyl radicals.
  • Preferred alkylamino radicals are "lower alkylamino" radicals having one to six carbon atoms. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Examples of such lower alkylamino radicals include N,N-dimethylamino, and N,N-diethylamino.
  • Carbonyl is also used herein synonymously with the term “oxo”.
  • alkylthio or "thioalkoxy” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
  • An example of “alkylthio” or “thioalkoxy” is methylthio,(CH 3 S-).
  • Form I includes any sub formulas, such as Formulas I-A, I-A-I and Formulas I-B-I.
  • pharmaceutically-acceptable when used with reference to a compound of Formulas I, I-A, I-A-I and I-B-I is intended to refer to a form of the compound that is safe for administration.
  • a salt form, a solvate, or a hydrate form of a compound of Formulas I, I-A, I-A-I and I-B- which has been approved for mammalian use, via oral ingestion or other routes of administration, by a governing body or regulatory agency, such as the Food and Drug Administration (FDA) of the United States, is pharmaceutically acceptable.
  • FDA Food and Drug Administration
  • salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • salts may be formed from ionic associations, charge-charge interactions, covalent bonding, complexation, coordination, etc. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of Formulas I, I-A, I-A-I and I-B-I may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include, without limitation, formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formulas I, I-A and I-B include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including, without limitation, primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, disopropylethylamine and trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formulas I, I-A, I-A-I and I-B-I.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such as de
  • a phosphate salt of a compound of the invention may be made by combining the desired compound free base in a desired solvent, or combination of solvents, with phosphoric acid in a desired stoichiometric amount, at a desired temperature, typically under heat (depending upon the boiling point of the solvent).
  • the salt can be precipitated upon cooling (slow or fast) and may crystallize (i.e., if crystalline in nature), as appreciated by those of ordinary skill in the art.
  • hemi-, mono-, di, tri- and poly-salt forms of the compounds of the present invention are also contemplated herein.
  • hemi-, mono-, di, tri- and poly-hydrated forms of the compounds, salts and derivatives thereof, are also contemplated herein.
  • the compound(s) of Formulas I, I-A, I-A-I and I-B-I may be used to treat a subject by administering the compound(s) as a pharmaceutical composition.
  • the compound(s) can be combined with one or more excipients, including carriers, diluents or adjuvants to form a suitable composition, which is described in more detail herein.
  • excipient denotes any pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration purposes.
  • API active pharmaceutical ingredient
  • treat refers to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy.
  • Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals.
  • an effective dosage amount is intended to quantify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. Accordingly, this term is not limited to a single dose, but may comprise multiple dosages required to bring about a therapeutic or prophylactic response in the subject.
  • “effective dosage amount” is not limited to a single capsule or tablet, but may include more than one capsule or tablet, which is the dose prescribed by a qualified physician or medical care giver to the subject.
  • LG generally refers to groups that are displaceable by a nucleophile.
  • Such leaving groups are known in the art. Examples of leaving groups include halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH 3 ), N-hydroxsuccinimide, and N-hydroxybenzotriazole.
  • Nucleophiles are species that are capable of attacking a molecule at the point of attachment of the leaving group causing displacement of the leaving group. Nucleophiles are known in the art. Examples of nucleophilic groups include, amines, thiols, alcohols, Grignard reagents, and anionic species (e.g., alkoxides, amides, carbanions).
  • the present invention further comprises procedures for the preparation of compounds of Formulas I, I-A, I-A-I and I-B-I.
  • the compounds of Formulas I, I-A, I-A-I and I-B-I can be synthesized according to the procedure described in Scheme 1, wherein the substituents are as defined for Formulas I, I-A, I-A-I and I-B-I above, except where further noted.
  • the compounds of the present invention may also be prepared according to one or more of the methods, and/or steps described therein, as described in examples 1-57 herein. To this end, the synthetic methods described below are merely exemplary, and the compounds of the invention may further be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art.
  • 6-Bromo-2-chloro quinoline 1 may be purchased or made separated by known published methods, as discussed hereinbelow) may be converted to 6-bromo-3-iodo-2-chloro quinoline 2 , using a suitable iodine source and reaction conditions, such as convention conditions.
  • a suitable iodine source and reaction conditions such as convention conditions.
  • Example 1 describes one method of preparing compound 2 .
  • the chloro group of compound 2 may be displaced with a suitably protected amine, such as as shown above, by 4-methoxybenzylamine, under suitable conditions to afford the protected amino-quinoline 3 .
  • the iodo group of compound 3 may then be displaced with morpholine under suitable conditions, such as those described in Example 1 below, which utilize a copper catalyst, to afford the 3-morpholino-quinline intermediate 4 , as shown above.
  • Morpholine is merely an exemplary N-linked saturated or partially saturated, optionally substituted ring Z which may be installed at position 3 of the quinoline ring. Though scheme 1 illustrates a morpholine as ring Z, the present invention is not so limited, and other rings defined herein may be at this position on the amino-quinoline core ring of Formulas I, I-A and I-A-I.
  • Intermediate 4 may then converted to a more active reagent via conversion of the bromide to a corresponding boronic acid derivative, such the doxolo-borane intermediate 5 shown above.
  • One method of preparing compound 5 is described in Example 1 below.
  • the boronic acid, and/or ester, intermediates 5 may be prepared by methods described in the following references: (1) PCT Int. Patent Appl. No. WO 2005073189 , titled “Preparation of fused heteroaryl derivatives as p38 kinase inhibitors” or (2) PCT Int. Patent Appl. No. WO 2006094187 , titled "Preparation of phthalazine, aza- and diazaphthalazine compounds as protein kinase, especially p38 kinase, inhibitors for treating inflammation and related conditions". Also, desired boronic acids may be commercially purchased or internally prepared as needed.
  • the boronate ester 5 can then be displaced by suitable aromatic bromides, such as bromo-phenyl compounds, to afford the corresponding desirable 6-substituted protected quinoline amines 6 .
  • Compound 6 may be prepared using conventional Suzuki or Suzuki-like reaction conditions and reagents. Suzuki reactions are a known type of reaction involving a boronic acid reagent and a suitable aromatic bromide, such as the Br-aromatic ring A (Br is a suitable halogen leaving group "LG"). As appreciated to one of ordinary skill in the art, Suzuki and Suzuki-like reactions also utilize a palladium catalyst.
  • Suitable palladium catalysts include, without limitation, Pd(PPh 3 ) 4 , Pd(OAc) 2 or Pd(dppf)Cl 2 .
  • the halide may be an iodide, a bromide or even a chloride.
  • Chloro-pyridyl rings undergo Suzuki reactions in the presence of Pd(OAc) 2 .
  • Other LGs are also suitable.
  • Suzuki couplings are known to occur with a sulfonate, such as trifluoromethanesulfonate, as the leaving group.
  • the Suzuki reaction conditions may vary.
  • Suzuki reactions are run generally in the presence of a suitable base such as a carbonate base, bicarbonate or an acetate base, in a suitable solvent such as toluene, acetonitrile, DMF or an aqueous-organic solvent combination or a biphasic system of solvents.
  • a suitable base such as a carbonate base, bicarbonate or an acetate base
  • a suitable solvent such as toluene, acetonitrile, DMF or an aqueous-organic solvent combination or a biphasic system of solvents.
  • the reaction may simply require solvent and heat depending upon the particular bromide 3 and/or boronic acid or ester, as appreciated by those skilled in the art.
  • Other methods of installing the boronate on a desired aromatic ring are known.
  • metal coupling chemistry such Stille, Kumada, Negishi coupling methods, and the like, may be employed to prepare desired products 6 .
  • crude product-containing residues were purified by passing the crude material orconcentrate through an ISCO brand silica gel column (prepacked or individually packed with SiO 2 ) and eluting the product off the column with a solvent gradient as indicated.
  • ISCO brand silica gel column prepacked or individually packed with SiO 2
  • eluting the product off the column with a solvent gradient as indicated.
  • a description of (330 g SiO 2 , 0-40% EtOAc/Hexane) means the product was obtained by elution from the column packed with 330gms of silica, with a solvent gradient of 0% to 40% EtOAc in Hexanes.
  • the compounds described herein were purified via reverse phase HPLC using one of the following instruments: Shimadzu, varian, Gilson; utilizing one of the following two HPLC columns: (a) a Phenomenex Luna or (b) a Gemini column (5 micron or 10 micron, C18, 150x50 mm)
  • a microwave vial was charged with (2-(2-amino-3-morpholinoquinolin-6-yl)-3-chlorophenyl)(pyrrolidin-1-yl)methanone (273 mg, 0.625 mmol, see Example 42), dichlorobis(acetonitrile)-palladium(II) (24.31 mg, 0.094 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (134 mg, 0.281 mmol) and cesium carbonate (529 mg, 1.625 mmol). The vial was evacuated and backfilled with nitrogen gas 2x.
  • Table I The following examples in Table I were prepared by methods analogous to those described in Examples 1-57 above. Provided also is the mass spectral data and BACE enzyme and cell-based assay data (IC 50 's in uM ranges) for each example, where available.
  • the compounds of Example No. 57, 61 and 206 in Table 1 are reference compounds. Table 1 Ex. No.
  • the present invention also provides methods for making compounds of Formulas I, 1-A, I-A-I and 1-B-I.
  • a method of making a compound of Formula I comprising the steps of (a) reacting a compound 17 wherein B 1 , ring Z, R 2 and n of Formula I are as defined herein, with a compound having the structure wherein ring A, R 1 and m are as defined herein to make a compound 18 of the formula and (b) deprotecting compound 18 to make a compound 19 of formula I
  • the steps may be preceded, or followed, by additional protection/deprotection steps as necessary.
  • one or more functional groups for example carboxy, hydroxy, amino, or mercapto groups
  • various known conventional protecting groups may be used.
  • protecting groups typically utilized in the synthesis of natural and synthetic compounds including peptides, nucleic acids, derivatives thereof and sugars, having multiple reactive centers, chiral centers and other sites potentially susceptible to the reaction reagents and/or conditions, may be used.
  • Synthetic chemistry transformations and protecting group methodologies useful in synthesizing the inhibitor compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989 ); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons (1999 ); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994 ); A. Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2nd edition (2001 ); M. Bodanszky, A.
  • Bodanszky The Practice of Peptide Synthesis, Springer-Verlag, Berlin Heidelberg (1984 ); J. Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd edition, Wiley-VCH, (1997 ); and L. Paquette, editor, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995 ).
  • Salts, including pharmaceutically acceptable salts, of a compound of the invention having a salt-forming group may be prepared in a conventional manner or manner known to persons skilled in the art.
  • acid addition salts of compounds of the invention may be obtained by treatment with an acid or with a suitable anion exchange reagent.
  • a salt with two acid molecules for example a dihalogenide
  • a salt with one acid molecule per compound for example a monohalogenide
  • this may be done by heating to a melt, or for example by heating as a solid under a high vacuum at elevated temperature, for example from 50 °C to 170 °C, one molecule of the acid being expelled per molecule of the compound.
  • Acid salts can usually be converted to free-base compounds, e.g. by treating the salt with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • suitable basic agents for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • the ability of the solvent to allow and/or influence the progress or rate of the reaction is generally dependant on the type and properties of the solvent(s), the reaction conditions including temperature, pressure, atmospheric conditions such as in an inert atmosphere under argon or nitrogen, and concentration, and of the reactants themselves.
  • Suitable solvents for conducting reactions to synthesize compounds of the invention include, without limitation, water; esters, including lower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphatic ethers, e.g., Et 2 O and ethylene glycol dimethylether or cyclic ethers, e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene and xylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- and t-butanol; nitriles including CH 3 CN; halogenated hydrocarbons, including CH 2 Cl 2 , CHCl 3 and CCl 4 ; acid amides including DMF; sulfoxides, including DMSO; bases, including heterocyclic nitrogen bases, e.g.
  • carboxylic acids including lower alkanecarboxylic acids, e.g., AcOH
  • inorganic acids including HCl, HBr, HF, and H 2 SO 4
  • carboxylic acid anhydrides including lower alkane acid anhydrides, e.g., acetic anhydride
  • cyclic, linear, or branched hydrocarbons including cyclohexane, hexane, pentane, and isopentane, and mixtures of these solvents, such as purely organic solvent combinations, or water-containing solvent combinations e.g., aqueous solutions.
  • solvents and solvent mixtures may also be used in "working-up" the reaction as well as in processing the reaction and/or isolating the reaction product(s), such as in chromatography.
  • Purification methods include, for example, crystallization, chromatography (liquid and gas phase), extraction, distillation, trituration, and reverse phase HPLC. Reactions conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient) are known in the art and may be adjusted as appropriate for the reaction.
  • Compounds of the present invention can possess, in general, one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. While shown without respect to stereochemistry in Formulas I, I-A and I-B, the present invention includes such optical isomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base.
  • appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound.
  • the optically active compounds of the invention can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. All such isomeric forms of such compounds are expressly included in the present invention.
  • the compounds of the invention may also be represented in multiple tautomeric forms. Tautomers often exist in equilibrium with each other, and interconvert under environmental and physiological conditions.
  • the compounds of the invention may also occur in cis- or trans- or E- or Z- double bond isomeric forms.
  • the invention expressly includes all tautomeric forms of the compounds described herein.
  • the present invention also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine such as 2 H, 3 H 13 C, 14 C 15 N, 16 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detection.
  • Isotopically labelled compounds of this invention can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds of the invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • the compounds of the present invention exhibit improved pharmacokinetics and pharmacodynamics, which relate, directly and indirectly, to the ability of the compound to be effective for its intended use.
  • the compounds have been found to possess favorable clearance and efflux properties, which readily lend themselves to projecting in-vivo PK and PD properties, which in turn assist in projection of therapeutic target coverage for the compounds and projected efficacious dosages via in-vivo absorption, distribution, metabolism and excretion properties.
  • Increased biological penetration into a given biological compartment e.g., blood, lymphatic system, central nervous system
  • increase oral availability increase solubility to allow administration by injection and alter clearance, metabolism and/or rate of excretion are important factors for discovering which compound may be a useful drug and which may not.
  • the assay buffer used in this screen is 0.05 M acetate, pH 4.2, 10% DMSO final, 100 uM genapol (which is a nonionic detergent, below its Critical Micelle Concentration).
  • the beta secretase enzyme (0.2nM) is pre-incubated for one hour with inhibitors, typically in about 1uL of DMSO according to a serial dilution, are added thereto.
  • the assay is effectively started by the addition of FRET substrate (50nM) and the combination is incubated for one hour.
  • the FRET assay is terminated with by addition of Tris buffer, which raises the pH to neutrality, and the fluorescence is determined.
  • the FRET substrate is a peptide with commercially available fluorophore and quencher, on opposite sides of the BACE cleavage site. Proteolytic cleavage of the FRET substrate releases quenching of fluorescence (excitation 488 nm and emission 425 nm).
  • the cell-based assay measures inhibition or reduction of A ⁇ 40 in conditioned medium of test compound treated cells expressing amyloid precursor protein.
  • APP Amyloid Precursor Protein
  • the sandwich ELISA to detect A ⁇ 40 was performed in 96 well microtiter plates, which were pre-treated with goat anti-rabbit IgG (Pierce).
  • the capture and detecting antibody pair that were used to detect A ⁇ 40 from cell supernatants were affinity purified pAb40 (Biosource) and biotinylated 6E10 (Signet Labs Inc.), respectively.
  • the optimal concentration for the pAb40 antibody was 3 ⁇ g/ml in Superblock/TBS (Pierce) that was supplemented with 0.05%Tween 20 (Sigma).
  • Optimal concentration for the detection antibody 6E10-biotinylated was 0.5 ⁇ g/ml in Superblock/TBS (Pierce) that had been supplemented with 2% normal goat serum and 2 % normal mouse serum.
  • Animal models including mouse, rat, dog, and monkey, may be used to screen for inhibition of beta-secretase activity in vivo following administration of a test compound sample.
  • Animals used in this invention can be wild type, transgenic, or gene knockout animals.
  • the Tg2576 mouse model prepared and conducted as described in Hsiao et al., 1996, Science 274, 99-102 , and other non-transgenic or gene knockout animals are useful to analyze in vivo inhibition of Amyloid beta peptide (Abeta) production in the presence of inhibitory test compounds.
  • Abeta Amyloid beta peptide
  • mice 2 to 18 month old Tg2576 mice, gene knockout mice or non-transgenic animals are administered test compounds formulated in vehicles, such as cyclodextran, phosphate buffers, hydroxypropyl methylcellulose or other suitable vehicles.
  • test compounds formulated in vehicles such as cyclodextran, phosphate buffers, hydroxypropyl methylcellulose or other suitable vehicles.
  • animals are sacrificed, and brains as well as cerebrospinal fluid (CSF) and plasma are removed for analysis of A-beta levels and drug or test compound concentrations ( Dovey et al., 2001, Journal of Neurochemistry, 76,173-181 ) Beginning at time 0, animals are administered by oral gavage, or other means of delivery such as intravenous injection, an inhibitory test compound of up to 100 mg/kg in a standard, conventional formulation, such as 2% hydroxypropyl methylcellulose, 1% Tween80.
  • CSF cerebrospinal fluid
  • a separate group of animals receive 2% hydroxypropyl methylcellulose, 1% Tween80 alone, containing no test compound, and serve as a vehicle-control group.
  • animals are sacrificed and brain tissues, plasma or cerebrospinal fluid are collected. Brains are either homogenized in 10 volumes (w/v) of 0.2% diethylamine (DEA) in 50 mM NaCl ( Best et al., 2005, Journal of Pharmacology and Experimental Therapeutics, 313, 902-908 ), or in 10 volumes of 0.5% TritonX-100 in Tris-buffered saline (pH at about 7.6). Homogenates are centrifuged at 355,000g, 4°C for 30 minutes.
  • DEA diethylamine
  • rat Abeta40 is measured using biotinylated-4G8 (Signet) as a capture antibody and Fab40 (an in-house antibody specific to the C-terminal of Abeta40) as a detection antibody.
  • biotinylated-4G8 Signet
  • Fab40 an in-house antibody specific to the C-terminal of Abeta40
  • compounds of the invention are useful for the prevention or treatment of beta-secretase related diseases, including Alzheimer's disease.
  • the compounds of the invention have the ability to modulate the activity of beta secretase enzyme, thereby regulating the production of amyloid beta (Abeta peptide) and reducing the formation and deposition of Abeta peptide and/or plaque on the brain.
  • beta secretase enzyme thereby regulating the production of amyloid beta (Abeta peptide) and reducing the formation and deposition of Abeta peptide and/or plaque on the brain.
  • the present specification discloses a method of treating a disorder related to a beta-secretase enzyme in a subject, the method comprising administering to the subject an effective dosage amount of a compound of Formulas I, 1-A, I-A-I and 1-B-I.
  • a disorder related to a beta-secretase enzyme in a subject, the method comprising administering to the subject an effective dosage amount of a compound of Formulas I, 1-A, I-A-I and 1-B-I.
  • the present specification discloses a method of reducing production of amyloid beta, and of reducing plaque formation.
  • the present specification discloses a method for the treatment, prevention or amelioration of a disease or disorder characterized by the elevated beta-amyloid deposits or beta-amyloid levels in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any of Formulas I, 1-A, I-A-I and 1-B-I.
  • the present specification discloses a method of treating Alzheimer's disease, cognitive impairment including mild, moderate and/or severe, Down's Syndrome, cognitive decline, senile dementia, cerebral amyloid angiopathy or a neurodegenerative disorder.
  • these compounds are useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, and rodents.
  • animals including horses, dogs, and cats may be treated with compounds provided by the invention.
  • Treatment of diseases and disorders herein is intended to also include therapeutic administration of a compound of the invention, or a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject ( i.e ., an animal, preferably a mammal, most preferably a human) which may be in need of preventative treatment, such as, for example, for pain, and inflammation.
  • Treatment also encompasses prophylactic administration of a compound of the invention, or a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject ( i.e ., an animal, preferably a mammal, most preferably a human).
  • the subject is initially diagnosed by a licensed physician and/or authorized medical practitioner, and a regimen for prophylactic and/or therapeutic treatment via administration of the compound(s) or compositions of the invention is suggested, recommended or prescribed.
  • the amount of compound(s) which is/are administered and the dosage regimen for treating neurological disorders and beta-secretase mediated diseases with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods.
  • a daily dose of about 0.01 to 500 mg/kg, advantageously between about 0.01 and about 50 mg/kg, more advantageously about 0.01 and about 30 mg/kg, and even more advantageously between about 0.1 and about 10 mg/kg body weight may be appropriate, and should be useful for all compounds for use disclosed herein.
  • the daily dose can be administered in one to four doses per day.
  • a pharmaceutical composition comprising a compound of this invention in combination with a pharmaceutically acceptable carrier, which includes diluents, and excipients as described herein.
  • a pharmaceutical composition of the invention may comprise an effective amount of a compound of the invention or an effective dosage amount of a compound of the invention.
  • An effective dosage amount of a compound of the invention includes an amount less than, equal to or greater than an effective amount of the compound; for example, a pharmaceutical composition in which two or more unit dosages, such as in tablets, and capsules, are required to administer an effective amount of the compound, or alternatively, a multidose pharmaceutical composition, such as powders, and liquids, in which an effective amount of the compound is administered by administering a portion of the composition.
  • a pharmaceutical composition in which two or more unit dosages, such as in tablets, and capsules, are required to administer an effective amount of the compound may be administered in less than an effective amount for one or more periods of time, for example to ascertain the effective dose for an individual subject, to desensitize an individual subject to potential side effects, to permit effective dosing readjustment or depletion of one or more other therapeutics administered to an individual subject.
  • the compound(s) of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds and compositions of the present invention may, for example, be administered orally, mucosally, topically, rectally, pulmonarily such as by inhalation spray, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly intrasternally and infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are tablets or capsules.
  • these may contain an amount of active ingredient from about 1 to 2000 mg, advantageously from about 1 to 500 mg, and typically from about 5 to 150 mg.
  • a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods and practices.
  • the active compounds of this invention are ordinarily combined with one or more adjuvants or other "excipients" appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, to form the final formulation.
  • the active compound(s) and excipient(s) may be tableted or encapsulated by known and accepted methods for convenient administration.
  • suitable formulations include, without limitation, pills, tablets, soft and hard-shell gel capsules, troches, orally-dissolvable forms and delayed or controlled-release formulations thereof.
  • capsule or tablet formulations may contain one or more controlled-release agents, such as hydroxypropylmethyl cellulose, as a dispersion with the active compound(s).
  • Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • the active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (ie. Tween 80).
  • suitable carriers including saline, dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (ie. Tween 80).
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water.
  • suitable carriers including saline, dextrose, or water.
  • the daily parenteral dosage regimen will be from about 0.1 to about 30 mg/kg of total body weight, and preferably from about 0.1 to about 10 mg/kg.
  • the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler including dry powder aerosol.
  • compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents. Accordingly, in yet another embodiment of the present invention, there is provided a method of manufacturing a medicament, the method comprising combining an amount of a compound according to Formulas I, 1-A, I-A-I and 1-B-I with a pharmaceutically acceptable carrier to manufacture the medicament.
  • the invention provides a method of manufacturing a medicament for the treatment of Alzheimer's disease, the method comprising combining an amount of a compound according to Formulas I, 1-A, I-A-I and 1-B-I with a pharmaceutically acceptable carrier to manufacture the medicament.
  • the compounds of the invention can be dosed or administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or in conjunction with other agents.
  • the therapeutic agents can be formulated as separate compositions that are administered simultaneously or sequentially at different times, or the therapeutic agents can be given as a single composition.
  • co-therapy in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace coadministration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
  • the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of beta-secretase, gamma-secretase and/or other reagents known in influence the formation and/or deposition of amyloid beta, otherwise responsible for the formation of plaque on the brain.
  • Compounds of Formulas I, I-A and I-B may also be administered sequentially with known anti-inflammatory agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; compounds of the invention may be administered either prior to, simultaneous with or after administration of the known anti-inflammatory agent.

Claims (12)

  1. Verbindung der Formel I:
    Figure imgb0084
     oder ein Stereoisomer oder ein pharmazeutisch verträgliches Salz derselben, wobei
    A ein 5- oder 6-gliedriger Aryl- oder Heterarylring ist;
    jedes aus B1, B2 und B3 unabhängig voneinander N, -CF, -CCH3 oder CH ist;
    jedes R1 unabhängig voneinander Halogen, Halogenalkyl, CN, OH, NO2, NH2, Acetyl, C110-Alkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Cycloalkyl, C4-10-Cycloalkenyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Alkoxyl, C1-10-Thioalkoxyl, -C(O)C1-6-Alkyl, -C(O)-Cycloalkyl, -C(=N-OH)-R3, -C(=N-OCH3)-R3, -C(O)OR3 oder -C(O)NRaRb ist, wobei Ra H oder C1-6Alkyl ist und Rb R3 ist, alternativ, Ra und Rb zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4-7-gliedrigen monocyclischen Heterocyclus bilden, der optional mit 1-3 Substituenten aus R3 substituiert ist; oder
    R1 ein vollständig gesättigtes oder teilweise oder vollständig ungesättigtes 3-8-gliedriges monocyclisches oder ein 6-12-gliedriges bicyclisches Ringsystem ist, wobei das Ringsystem aus Kohlenstoffatomen gebildet ist und optional 1-3 Heteroatome enthält, wenn es monocyclisch ist, oder 1-6 Heteroatome, wenn es bicyclisch ist, wobei die Heteroatome aus O, N, oder S ausgewählt sind,
    wobei jedes aus C1-10-Alkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Cycloalkyl, C4-10-Cycloalkenyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Alkoxyl, C1-10-Thioalkoxyl und dem Ring des Ringsystems optional unabhängig voneinander mit 1-5 Substituenten aus R3 substituiert ist;
    jedes R2 unabhängig voneinander Halogen, Halogenalkyl, Halogenalkoxyl, CN, NO2, NH2, OH, Oxo, C1-6-Alkyl, -OC1-6-Alkyl, -S(O)nC1-6-Alkyl, -NHC1-6-Alkyl, Aryl oder -C(O)NRaRb ist, wobei Ra H oder C1-6Alkyl ist und Rb H oder C1-6Alkyl ist;
    jedes R3 unabhängig voneinander Halogen, Halogenalkyl, CN, OH, NO2, NH2, Acetyl, Oxo, C1-10-Alkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Cycloalkyl, C4-10-Cycloalkenyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Alkoxyl, C1-10-Thioalkoxyl oder ein vollständig gesättigtes oder teilweise oder vollständig ungesättigtes 3-8-gliedriges monocyclisches oder ein 6-12-gliedriges bicyclisches Ringsystem ist, wobei das Ringsystem aus Kohlenstoffatomen gebildet ist und optional 1-3 Heteroatome enthält, wenn es monocyclisch ist, oder 1-6 Heteroatome, wenn es bicyclisch ist, wobei die Heteroatome aus O, N, oder S ausgewählt sind, wobei jedes aus C1-10-Alkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Cycloalkyl, C4-10-Cycloalkenyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Alkoxyl, C1-10-Thioalkoxyl und dem Ring des Ringsystems optional unabhängig voneinander mit 1-5 Substituenten aus Halogen, Halogenalkyl, Halogenalkoxyl, CN, NO2, NH2, OH, Oxo, Methyl, Methoxyl, Ethyl, Ethoxyl, Propyl, Propoxyl, Isopropyl, Isopropoxyl, Cyclopropyl, Cyclopropylmethoxyl, Butyl, Butoxyl, Isobutoxyl, tert-Butoxyl, Isobutyl, sec-Butyl, tert-Butyl, Cyclobutyl, Pentyl, Cyclopentyl, Hexyl, Cyclohexyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Thioalkoxyl, Benzyl oder Phenyl substituiert ist;
    wobei Ring Z
    Figure imgb0085
    Figure imgb0086
     ist, wobei jeder dieser Ringe optional unabhängig voneinander mit 1-5 Substituenten aus R2 substituiert ist;
    m 0, 1, 2, 3, 4 oder 5 ist; und
    n 0, 1, 2, 3, 4 oder 5 ist.
  2. Verbindung nach Anspruch 1, oder ein Stereoisomer oder pharmazeutisch verträgliches Salz derselben, wobei Ring A ein Phenyl-, Pyridin-, Pyrimidin-, Triazin-, Pyrazinyl-, Pyridazinyl- oder Thiophen-Ring ist.
  3. Verbindung nach Anspruch 1, oder ein Stereoisomer oder pharmazeutisch verträgliches Salz derselben mit der Formel I-A
    Figure imgb0087
     wobei
    B1 -CF, -CCH3 oder CH ist;
    jedes R1 unabhängig voneinander Halogen, Halogenalkyl, CN, OH, NO2, NH2, Acetyl, C110-Alkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Cycloalkyl, C4-10-Cycloalkenyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Alkoxyl, C1-10-Thioalkoxyl, -C(O)C1-6-Alkyl, -C(O)-Cycloalkyl, -C(=N-OH)-R3,-C(=N-OCH3)-R3 oder -C(O)NRaRb ist, wobei Ra H oder C1-6Alkyl ist und Rb R3 ist, alternativ, Ra und Rb zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4-7-gliedrigen monocyclischen Heterocyclus bilden, der optional mit 1-3 Substituenten aus R3 substituiert ist; oder
    R1 ein vollständig gesättigtes oder teilweise oder vollständig ungesättigtes 3-8-gliedriges monocyclisches oder ein 6-12-gliedriges bicyclisches Ringsystem ist, wobei das Ringsystem aus Kohlenstoffatomen gebildet ist und optional 1-3 Heteroatome enthält, wenn es monocyclisch ist, oder 1-6 Heteroatome, wenn es bicyclisch ist, wobei die Heteroatome aus O, N, oder S ausgewählt sind,
    wobei jedes aus C1-10-Alkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Cycloalkyl, C4-10-Cycloalkenyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Alkoxyl, C1-10-Thioalkoxyl und dem Ring des Ringsystems optional unabhängig voneinander mit 1-5 Substituenten aus R3 substituiert ist;
    jedes R2 unabhängig voneinander F, Cl, CF3, OCF3, C1-6-Alkyl, CN, OH, -OC1-6-Alkyl, -OCF3, -NH2, NHCH3 oder -C(O)CH3 ist;
    jedes R3 unabhängig voneinander Halogen, Halogenalkyl, CN, OH, NO2, NH2, Acetyl, Oxo, C1-10-Alkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Cycloalkyl, C4-10-Cycloalkenyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Alkoxyl, C1-10-Thioalkoxyl oder ein vollständig gesättigtes oder teilweise oder vollständig ungesättigtes 3-8-gliedriges monocyclisches oder ein 6-12-gliedriges bicyclisches Ringsystem ist, wobei das Ringsystem aus Kohlenstoffatomen gebildet ist und optional 1-3 Heteroatome enthält, wenn es monocyclisch ist, oder 1-6 Heteroatome, wenn es bicyclisch ist, wobei die Heteroatome aus O, N, oder S ausgewählt sind, wobei jedes aus C1-10-Alkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Cycloalkyl, C4-10-Cycloalkenyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Alkoxyl, C1-10-Thioalkoxyl und dem Ring des Ringsystems optional unabhängig voneinander mit 1-5 Substituenten aus Halogen, Halogenalkyl, Halogenalkoxyl, CN, NO2, NH2, OH, Oxo, Methyl, Methoxyl, Ethyl, Ethoxyl, Propyl, Propoxyl, Isopropyl, Isopropoxyl, Cyclopropyl, Cyclopropylmethoxyl, Butyl, Butoxyl, Isobutoxyl, tert-Butoxyl, Isobutyl, sec-Butyl, tert-Butyl, Cyclobutyl, Pentyl, Cyclopentyl, Hexyl, Cyclohexyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Thioalkoxyl, Benzyl oder Phenyl substituiert ist;
    wobei Ring Z
    Figure imgb0088
    Figure imgb0089
     ist, wobei jeder dieser Ringe optional unabhängig voneinander mit 1-5 Substituenten aus R2 substituiert ist;
    m 1, 2 oder 3 ist; und
    n 0, 1 oder 2 ist.
  4. Verbindung nach Anspruch 3 oder ein Stereoisomer oder ein pharmazeutisch verträgliches Salz derselben mit der Formel I-A-I
    Figure imgb0090
     wobei
    B1 -CF, -CCH3 oder CH ist;
    jedes R1 unabhängig voneinander Halogen, Halogenalkyl, CN, OH, NO2, NH2, Acetyl, C16-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-7-Cycloalkyl, C4-7-Cycloalkenyl, C1-6-Alkylamino-, C1-6-Dialkylamino-, C1-6-Alkoxyl, C1-6-Thioalkoxyl, -C(O)-R3, -C(O)NHR3, -C(O)OR3 oder -C(O)NRaRb ist, wobei Ra H oder C1-6Alkyl ist, und Rb R3 ist, alternativ, Ra und Rb zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4-7-gliedrigen monocyclischen Heterocyclus bilden, der optional mit 1-3 Substituenten aus R3 substituiert ist; oder
    R1 ein vollständig gesättigtes oder teilweise oder vollständig ungesättigtes 3-8-gliedriges monocyclisches oder ein 6-12-gliedriges bicyclisches Ringsystem ist, wobei das Ringsystem aus Kohlenstoffatomen gebildet ist und optional 1-3 Heteroatome enthält, wenn es monocyclisch ist, oder 1-6 Heteroatome, wenn es bicyclisch ist, wobei die Heteroatome aus O, N, oder S ausgewählt sind,
    wobei jedes aus C1-10-Alkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Cycloalkyl, C4-10-Cycloalkenyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Alkoxyl, C1-10-Thioalkoxyl und dem Ring des Ringsystems optional unabhängig voneinander mit 1-5 Substituenten aus R3 substituiert ist;
    jedes R2 unabhängig voneinander F, Cl, CF3, OCF3, C1-6-Alkyl, CN, OH, -OC1-6-Alkyl, -OCF3, -NH2, NHCH3 oder -C(O)CH3 ist;
    m 0 oder 1 ist; und
    n 0 oder 1 ist.
  5. Verbindung nach Anspruch 1, oder ein Stereoisomer oder ein pharmazeutisch verträgliches Salz derselben mit der Formel I-B-I
    Figure imgb0091
     wobei
    B1 -CF, -CCH3 oder CH ist;
    jedes R1 unabhängig voneinander Halogen, Halogenalkyl, CN, OH, NO2, NH2, Acetyl, C16-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-7-Cycloalkyl, C4-7-Cycloalkenyl, C1-6-Alkylamino-, C1-6-Dialkylamino-, C1-6-Alkoxyl, C1-6-Thioalkoxyl, -C(O)-R3, -C(O)NHR3, -C(O)OR3 oder -C(O)NRaRb ist, wobei Ra H oder C1-6Alkyl ist und Rb R3 ist, alternativ, Ra und Rb zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4-7-gliedrigen monocyclischen Heterocyclus bilden, der optional mit 1-3 Substituenten aus R3 substituiert ist; oder
    R1 ein vollständig gesättigtes oder teilweise oder vollständig ungesättigtes 3-8-gliedriges monocyclisches oder ein 6-12-gliedriges bicyclisches Ringsystem ist, wobei das Ringsystem aus Kohlenstoffatomen gebildet ist und optional 1-3 Heteroatome enthält, wenn es monocyclisch ist, oder 1-6 Heteroatome, wenn es bicyclisch ist, wobei die Heteroatome aus O, N, oder S ausgewählt sind,
    wobei jedes aus C1-10-Alkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Cycloalkyl, C4-10-Cycloalkenyl, C1-10-Alkylamino-, C1-10-Dialkylamino-, C1-10-Alkoxyl, C1-10-Thioalkoxyl und dem Ring des Ringsystems optional unabhängig voneinander mit 1-5 Substituenten aus R3 substituiert ist;
    jedes R2 unabhängig voneinander F, Cl, CF3, OCF3, C1-6-Alkyl, CN, OH, -OC1-6-Alkyl, -OCF3, -NH2, NHCH3 oder -C(O)CH3 ist;
    m 0 oder 1 ist; und
    n 0 oder 1 ist.
  6. Verbindung nach Anspruch 1, oder ein Stereoisomer oder pharmazeutisch verträgliches Salz derselben, ausgewählt aus
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(piperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(morpholino)methanon;
    (2-((2-Amino-3-(pyrrolidin-1-yl)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon; Ethyl 2-(2-amino-3-morpholinochinolin-6-yl)-3-methylbenzoat;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-propylpyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-tert-butylpyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-ethylpyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-isopropylpyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-methylpyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)methanon;
    (R)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3-fluoropyrrolidin-1-yl)methanon;
    (R)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-(methoxymethyl)pyrrolidin-1-yl)methanon;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-(2-methoxyethyl)-N, 3-dimethylbenzamid;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(4-methoxypiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(4-(methoxymethyl)piperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(4-(ethoxymethyl)piperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(4-(2-methoxyethyl)piperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(4-ethoxypiperidin-1-yl)methanon;
    (R)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3-methylpiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(4-propylpiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-propylpiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(4-methylpiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinotin-6-yl)-3-methylphenyl)(2-ethylpiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3-methoxypiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-(2-methoxyethyl)piperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)((2S,6R)-2,6-dimethylpiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3-ethoxypiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3,3-dimethylpiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-methylpiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3,5-dimethylpiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(thiazolidin-3-yl)methanonl;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2, 5-dihydro-1H-pyrrol-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(thiomorpholino)methanon;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-cyclopentyl-N,3-dimethylbenzamid;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(4-tert-butylpiperidin-1-yl)methanon;
    (S)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-(trifluoromethyl)pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(4-fluoropiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3-(trifluoromethyl)pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3,3-difluoropiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3,3-difluoropyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3,3-difluoroazetidin-1-yl)methanon;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N, 3-dimethyl-N-(2, 2, 2-trifluoroethyl)benzamid;
    (R)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3-methylpyrrolidin-1-yl)methanon;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N, N-diethyl-3-methylbenzamid;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(azetidin-1-yl)methanon;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-isobutyl-N,3-dimethylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-ethyl-3-methyl-N-propylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-isopropyl-3-methyl-N-propylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-cyclopropyl-N-ethyl-3-methylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N,3-dimethyl-N-(prop-2-inyl)benzamid;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(4,4-difluoropiperidin-1-yl)methanon;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N,3-dimethyl-N-propylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-(cyclopropylmethyl)-3-methyl-N-propylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-cyclohexyl-N,3-dimethylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-cyclohexyl-N-ethyl-3-methylbenzamid;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-(methylthio)-4,5-dihydro-1 H-imidazol-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3-methylpiperidin-1-yl)methanon;
    N, N-Diallyl-2-(2-amino-3-morpholinochinolin-6-yl)-3-methylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-butyl-N,3-dimethylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-butyl-N-ethyl-3-methylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-isopentyl-N,3-dimethylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N,3-dimethyl-N-(pentan-2-yl)benzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-ethyl-N,3-dimethylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N,3-dimethyl-N-(4-methylcyclohexyl)benzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-tert-butyl-N,3-dimethylbenzamid;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2,6-dimethylpiperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)methanon;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N,3-dimethyl-N-phenylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-3-methyl-N-phenylbenzamid;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-5-fluorophenyl)(azetidin-1-yl)methanon;
    Ethyl 2-(2-amino-3-morpholinochinolin-6-yl)-5-fluoro-3-methylbenzoat;
    (R)-(2-(2-Amino-3-morpholinochinolin-6-yl)-5-fluoro-3-methylphenyl)(3-fluoropyrrolidin-1-yl)methanon;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N,3-dimethyl-N-p-tolylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-(4-methoxyphenyl)-N,3-dimethylbenzamid;
    (R)-2-(2-Amino-3-morpholinochinolin-6-yl)-N,3-dimethyl-N-(1-phenylethyl)benzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N,N,3-trimethylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N,3-dimethyl-N-(naphthalen-1-ylmethyl)benzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-benzyl-N,3-dimethylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N,3-dimethyl-N-phenethylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-(4-fluorophenyl)-N,3-dimethylbenzamid;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N-(2-methoxyphenyl)-N,3-dimethylbenzamid;
    (2-((2-Amino-7-fluoro-3-morpholinochinolin-6-yl)phenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-6-chlorophenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-6-fluorophenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-chlorophenyl)(piperidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-chlorophenyl)(morpholino)methanon;
    Cyclopentyl 2-(2-amino-3-morpholinochinolin-6-yl)benzoat;
    Cyclopentyl 2-(2-amino-3-morpholinochinolin-6-yl)-3-methylbenzoat;
    (2-((2-Amino-3-morpholinochinolin-6-yl)phenyl)(tetrahydro-2H-pyran-4-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol;
    3-Morpholino-6-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)chinolin-2-amin;
    (2-((2-Amino-7-fluoro-3-morpholinochinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-7-fluoro-3-morpholinochinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-5-chlorophenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-fluorophenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)phenyl)(cyclopentyl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-4-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)phenyl)(phenyl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)phenyl)(cyclohexyl)methanon;
    1-((2-(2-Amino-3-morpholinochinolin-6-yl)phenyl)-3,3-dimethylbutan-1-on;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-4-chlorophenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-(trifluoromethyl)phenyl)(pyrrolidin-1-yl)methanon;
    1-((2-(2-Amino-3-morpholinochinolin-6-yl)phenyl)-2-cyclopentylethanone;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(o-tolyl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(phenyl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(pyridin-2-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(thiazol-2-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2-methoxyphenyl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3-chloropyridin-2-yl)methanon;
    6-((2-(3,4-Dihydroisochinolin-1-yl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    (2-((2-Amino-3-morpholinöchinolin-6-yl)-3-methylphenyl)(tetrahydrofuran-2-yl)methanon;
    6-((2-(Imino(2-methoxyphenyl)methyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-((1H-Imidazol-1-yl)(phenyl)methyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-Methyl-6-(phenyl(pyrrolidin-1-yl)methyl)phenyl)-3-morpholinochinolin-2-amin;
    6-((2-Methyl-6-(1,2,3,4-tetrahydroisochinolin-1-yl)phenyl)-3-morpholinochinolin-2-amin;
    6-((2-(3,3-Dimethylbut-1-inyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    2-((2-Amino-3-morpholinochinolin-6-yl)-N, 3-dimethyl-N-neopentylbenzamid;
    6-((2-(3,3-Dimethylbut-1-inyl)phenyl)-3-morpholinochinolin-2-amin;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-chlorophenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(2,2-dimethylmorpholino)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-(3,3-dimethylbut-1-inyl)phenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-(3,3-dimethylbutyl)phenyl)(pyrrolidin-1-yl)methanon;
    1-((2-(2-Amino-3-morpholinochinolin-6-yl)-3-(pyrrolidin-1-carbonyl)phenyl)-3,3-dimethylbutan-1-on;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-(phenylethinyl)phenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-phenethylphenyl)(pyrrolidin-1-yl)methanon;
    (S)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-(3,3-dimethylbutyl)phenyl)(3-fluoropyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-(3,3-dimethylbutyl)phenyl)(morpholino)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-(3,3-dimethylbutyl)phenyl)(azetidin-1-yl)methanon;
    (2-((2-Amino-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)chinolin-6-yl)-3-(3,3-dimethylbutyl)phenyl)(pyrrolidin-1-yl)methanon;
    (S)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-(3,3-dimethylbutyl)phenyl)(3-fluoropyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-(cyclohexylethinyl)phenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-(2-cyclohexylethyl)phenyl)(pyrrolidin-1-yl)methanon;
    4-((2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)morpholin-3-on;
    N-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)-N,3,3-trimethylbutanamid;
    6-((2-Methyl-6-(phenylamino)phenyl)-3-morpholinochinolin-2-amin;
    4-((2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)-6,6-dimethylmorpholin-3-on;
    3-Morpholino-6-(2-(neopentyloxy)phenyl)chinolin-2-amin;
    6-((2-Methyl-6-(neopentyloxy)phenyl)-3-morpholinochinolin-2-amin;
    6-((2-(Benzyloxy)phenyl)-3-morpholinochinolin-2-amin;
    6-((2-(Benzyloxy)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-Methyl-6-(tetrahydrofuran-3-yloxy)phenyl)-3-morpholinochinolin-2-amin;
    6-((2-(2-Isopropoxyethoxy)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-Methyl-6-phenoxyphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(3,3-Dimethylbutyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(m-tolyl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3-methoxypyridin-2-yl)methanon;
    3-(((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(2-(imino(2-methoxyphenyl)methyl)-6-methylphenyl)chinolin-2-amin;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(3-methylpyridin-2-yl)methanon;
    (E)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(phenyl)methanon-oxim;
    (Z)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(phenyl)methanon-oxim;
    (E)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(phenyl)methanon-O-methyl-oxim;
    (Z)-(2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(phenyl)methanon-O-methyl-oxim;
    (3-(((1,3-Dioxolan-2-yl)methyl)-2-(2-amino-3-morpholinochinolin-6-yl)phenyl)(pyrrolidin-1-yl)methanon;
    6-((2-(Amino(phenyl)methyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(Amino(o-tolyl)methyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(Amino(2-methoxyphenyl)methyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(Amino(pyridin-2-yl)methyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(Amino(3-chloropyridin-2-yl)methyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(Amino(3-methoxypyridin-2-yl)methyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(Amino(3-methylpyridin-2-yl)methyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(phenyl)methanol;
    6-((2-Benzyl-6-methylphenyl)-3-morpholinochinolin-2-amin;
    3-((2-(2-Amino-3-morpholinochinolin-6-yl)-3-methylbenzyl)benzonitrile;
    6-((2-(4-Fluorobenzyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(2-Fluorobenzyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(3-Methoxybenzyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(4-Chloro-1H-pyrazol-1-yl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((2-(4-Chloro-3-methyl-1H-pyrazol-1-yl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    3-Morpholino-6-(2-(4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)chinolin-2-amin;
    (2-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    6-((2-Methyl-6-(5-methyloxazol-2-yl)phenyl)-3-morpholinochinolin-2-amin;
    6-((2-Methyl-6-(4-methyloxazol-2-yl)phenyl)-3-morpholinochinolin-2-amin;
    6-((2-(Imidazo[1,5-a]pyridin-3-yl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    (2-((2-Amino-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-(tetrahydro-2H-pyran-2-yl)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-(tetrahydrofuran-2-yl)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-5-fluoro-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(1H-indol-1-yl)methanon;
    6-((2-((2-Chloro-5-(trifluoromethyl)phenoxy)methyl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    6-((3-Methyl-3'-(trifluoromethyl)biphenyl-2-yl)-3-morpholinochinolin-2-amin;
    (R)-(2-(2-Amino-3-(3-methylmorpholino)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-(2,3-dimethylmorpholino)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (S)-(2-(2-Amino-3-(3-methylmorpholino)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)chinolin-6-yl)-3-methylphenyl)(3,3-difluoropyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-(2-ethylmorpholino)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)chinolin-6-yl)-3-methylphenyl)(pyridin-2-yl)methanon;
    (2-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)chinolin-6-yl)-3-methylphenyl)(2-methoxyphenyl)methanon;
    6-((2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-6-methylphenyl)-3-morpholinochinolin-2-amin;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(pyrimidin-4-yl)methanon;
    (2-((2-Amino-3-morpholinochinolin-6-yl)-3-methylphenyl)(pyrazin-2-yl)methanol;
    6-((2-Methyl-6-(pyrazin-2-ylmethyl)phenyl)-3-morpholinochinolin-2-amin;
    (2-((2-Amino-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-(2-isobutylmorpholino)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-(2-(2-methoxyethyl)morpholino)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    (2-((2-Amino-3-(2,2-dimethylmorpholino)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    2-((2-Amino-3-(2,6-dimethylmorpholino)chinolin-6-yl)-N-ethyl-3-methyl-N-propylbenzamid;
    (2-((2-Amino-3-(2-methyl-2-p-tolylmorpholino)chinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanon;
    3-Morpholino-6-o-tolylchinolin-2-amin;
    6-((2-Chlorophenyl)-3-morpholinochinolin-2-amin;
    3-Morpholino-6-o-tolylchinolin-2-amin; und
    6-((2-Fluorophenyl)-3-morpholinochinolin-2-amin.
  7. Pharmazeutische Zusammensetzung, umfassend eine Verbindung nach einem der Ansprüche 1-6 und einen pharmazeutisch verträglichen Hilfsstoff.
  8. Verbindung nach einem der Ansprüche 1-6 zur Verwendung bei der Verringerung der Mengen von beta-Amyloid-Peptid in der Gehirn- und Rückenmarksflüssigkeit von einem Subjekt.
  9. Verbindung nach einem der Ansprüche 1-6 zur Verwendung bei der Behandlung der Alzheimer-Krankheit, einer kognitiven Beeinträchtigung oder einer Kombination derselben in einem Subjekt.
  10. Verbindung nach einem der Ansprüche 1-6 zur Verwendung bei der Behandlung einer neurologischen Störung, ausgewählt aus der Gruppe, bestehend aus milder kognitiver Beeinträchtigung, Down-Syndrom, hereditärer zerebraler Hämorrhagie mit Amyloidose vom holländischen Typ, zerebraler Amyloid-Angiopathie, degenerativer Demenz, mit der Parkinson-Krankheit assoziierte Demenz, mit supranukleärer Blickparese assoziierte Demenz, mit kortikaler basaler Degeneration assoziierter Demenz, Alzheimer-Krankheit vom diffusen Lewy-Körperchen-Typ oder einer Kombination derselben, in einem Subjekt.
  11. Verbindung nach einem der Ansprüche 1-6 zur Verwendung bei der Verringerung der Bildung von Plaque in dem Gehirn eines Subjekts.
  12. Verfahren zur Herstellung einer Verbindung der Formel I nach einem der Ansprüche 1-6, wobei das Verfahren die folgenden Schritte umfasst: (a) Umsetzen einer Verbindung 17
    Figure imgb0092
     wobei B1, Ring Z, R2 und n aus Formel I wie hier definiert sind, mit einer Verbindung mit der
    Struktur
    Figure imgb0093
     wobei Ring A, R1 und m wie hier definiert sind, um eine Verbindung 18 der Formel
    Figure imgb0094
     herzustellen; und
    (b) Entschützen der Verbindung 18, um eine Verbindung 19 der Formel I
    Figure imgb0095
     herzustellen.
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